Kinetic resolution (KR) is an established methodology for the preparation of enantioenriched compounds (see Scheme 1). In a chiral environment, for example in the presence of a chiral reagent B*, the enantiomers of a racemic mixture (A and A′) exhibit different reaction kinetics making it possible to modify one enantiomer (e.g. to provide A-B*) of the racemic mixture preferentially over the other. Thus, by preferentially modifying one of the enantiomers it is easy to separate it from the other enantiomer.

KR represents one of the most convenient methods for the rapid isolation of enantiopure alcohols by resolving the corresponding racemic materials via enantioselective acylation as shown in Scheme 2.

Initially, KR of racemic alcohols was carried out using biological catalysts such as enzymes. However, enzyme mediated catalysis can be troublesome on account of the low tolerance of enzymes to changes in pH and temperature. Furthermore, the incompatibility of enzymes with organic solvents vastly reduces the range of alcohol substrates that are suitable for acylation via enzyme mediated catalysis. Accordingly, in recent years several efficient and selective artificial organocatalysts for these processes have become available. As used herein organocatalysts are small molecule, non-metal containing catalysts that are soluble in organic solvents.
While the KR of alcohols is now a mature and useful technology, no analogous direct methods exist for the highly selective, direct catalytic KR of racemic thiols (i.e., R—SH)— despite the importance of thiols and organosulfur compounds in organic chemistry, and chemical biology.
Baker's yeast has been used to resolve a chiral thiol in the presence of glucose, however the resolved material was isolated in trace amounts only and with low enantioselectivity (40% ee). Reports disclosing lipase-catalysed transesterification of thioesters derived from racemic thiols are also acknowledged. Under optimal conditions the thiol products were obtained with high enantioselectivity (up to 95% ee). However, the latter is a multi-step methodology for the KR of thiols, only three thioester substrates were resolved, the methodology required long reaction times (up to 200 h) and high mass loadings of the enzyme catalyst.
International Patent Publication No. WO2009/050216 discloses a methodology for the dynamic kinetic resolution of thiols comprising utilising a hydrolase enzyme in the presence of an epimerisation catalyst. Notwithstanding these reports, enzymatic mediated resolution of thiols intrinsically suffers from the same problems as enzymatic resolution of alcohols discussed above.
While enantioenriched thiols can be synthesised from the corresponding alcohols, this simply makes one reliant on (and limited by) the availability of the desired alcohol substrate in enantiopure form. In addition, care must be exercised where a substrate (or its derivatives) is capable of racemisation.
For example, in attempting to prepare enantiopure thiols from the corresponding alcohols the present inventors found that subjecting commercially available (R)-1-phenyl-2-methyl-propanol (>99% ee) to a sequence involving mesylation, substitution with thioacetate ion (dry DMSO solvent, rt) and deprotection with LiAlH4 afforded (S)-1-phenyl-2-methyl-propanethiol in a substantially diminished enantiomeric excess of 84.5%, despite considerable care taken to try to avoid conditions favouring a competing SN1 substitution pathway (see Scheme 3).

The paucity of methodologies available for the catalytic asymmetric synthesis of enantioenriched thiols, and for the KR of thiols in particular, is attributable to the fact that, relative to alcohols, thiol substrates are inter alia ‘softer’ nucleophiles, exhibit greater atomic distance between the reacting heteroatom and the stereocentre and possess a lower heteroatom pKa.
Accordingly, it would be desirable to provide an organocatalytic enantioselective acylation protocol for the kinetic resolution of thiols, which mitigates the problems disclosed supra.